Volume 43 Issue 6, June 2011

A new study reveals that the HMG-box transcription factor SOX2 coupled with the chromatin remodeling helicase CHD7 cooperatively regulate target genes that are essential during neural stem cell development. Notably, this complex controls the expression of several disease-associated genes, suggesting a possible mechanistic connection between five seemingly unrelated human genetic disorders.

Genetic and gene expression studies have suggested an important role for KLF14 in metabolic disease. A new study now identifies a network of genes whose expression is associated with KLF14 variation in trans, providing a framework for understanding how KLF14 influences disease risk.

A genome-wide association study has identified two new loci modifying pulmonary disease severity in cystic fibrosis. Although this data offers clues to pathways influencing pulmonary function, the underlying genes and mechanisms remain to be elucidated.

Peter Visscher and colleagues report an analysis to partition the genetic variation for several complex traits onto chromosome segments and find that the variation explained is approximately proportional to the total length of genes included within a chromosome segment. They estimate that ~45%, ~17%, ~25% and ~21% of the phenotypic variation, respectively, for height, body mass index, von Willebrand factor and QT interval is tagged by common SNPs, and they partition this variation by chromosome and chromosome segments.

Nazneen Rahman and colleagues show that biallelic, loss-of-function mutations in CEP57 cause a constitutional mosaic aneuploidy syndrome. These findings show that CEP57 function is crucial for maintaining correct chromosomal number during cell division.

Norihiro Kato and colleagues perform a meta-analysis of genome-wide association studies to identify common variants associated with blood pressure variation in east Asians. They identify five new genome-wide significant signals and replicate seven loci previously discovered in populations of European ancestry.

Garry Cutting and colleagues report a genome-wide association and linkage study for loci that affect lung disease severity in cystic fibrosis. They identify two loci that influence lung function in individuals with cystic fibrosis.

Kathryn Anderson and colleagues use mouse genetics to define unexpected relationships between the retrograde ciliary motor gene Dync2h1 and other genes required for trafficking in primary cilia. Their findings argue that the mutant phenotypes in these models result from defects in cilia architecture rather than direct roles in signaling.

Ido Golding and colleagues examine transcriptional time series in Escherichia coli, characterizing mRNA copy number statistics for 20 promoters at single transcript resolution. They find that the degree of burstiness depends primarily on the level of gene expression.

Tim Spector, Mark McCarthy and colleagues show that an imprinted cis-acting regulatory variant of KLF14 previously associated with type 2 diabetes and HDL-cholesterol levels acts as a master trans regulator of adipose gene expression. The study provides a framework for understanding the effects of KLF14 on disease risk.

Karsten Suhre and colleagues report a genome-wide association study of metabolic traits in human urine, using NMR spectrometry to measure 59 metabolites in urine from participants. They identify five loci influencing urine metabolite levels and point to a missense variant in AGXT2 as the likely cause of hyper-β-aminoisobutyric aciduria, a common inborn error of metabolism.

Christopher Haiman and colleagues report a genome-wide association study for prostate cancer in African-American males drawn from 11 epidemiological studies of prostate cancer, with replication including individuals of African ancestry from 10 additional studies worldwide. They identify a new susceptibility locus on chromosome 17q21, for which the risk allele shows a higher frequency in men of African ancestry than in other populations. This may explain some of the increased incidence of prostate cancer in men of African ancestry.

Jamie Craig and colleagues report a genome-wide association study for advanced open angle glaucoma (OAG). They identify variants near TMCO1 and in CDKN2B-AS1 associated with OAG and show retinal expression of genes at both loci.

Simon John and Mounira Hmani-Aifa and colleagues show that mutation of the serine protease gene Prss56 causes elevated intraocular pressure and angle closure glaucoma in mice. They also identified PRSS56 mutations that cause posterior microphthalmia in humans.

Evan Eichler, Jay Shendure and colleagues sequenced the exomes of 20 sporadic cases of autism spectrum disorder and their unaffected parents. They identified potentially causative de novo mutations in four cases, including a frameshift in FOXP1, a splice-site mutation in GRIN2B and missense variants in SCN1A and LAMC3.

Murat Gunel and colleagues report the identification of mutations in the laminin γ3 gene that cause complex bilateral occipital cortical gyration abnormalities in humans.

Christopher Klein and colleagues report that DNMT1 is disrupted in hereditary sensory neuropathy with dementia and hearing loss. The mutations lead to reduced methyltransferase activity, leading to global hypomethylation and site-specific hypermethylation.

Tania Attié-Bitach and colleagues report that biallelic mutations in KIF7, a component of the Hedgehog signaling pathway, cause hydrolethalus and acrocallosal syndromes. They also present evidence that heterozygous KIF7 mutations contribute to the allelic load and phenotypic spectrum of other cilia disorders.

Raymond Poot and colleagues report that Chd7, a chromatin remodeler associated with CHARGE syndrome, and Sox2, a transcription factor associated with an anopthalmia syndrome, physically interact, have overlapping binding sites and regulate a set of common target genes.